Journal of Medicinal Studies 2016; 4(6): 173-180

ISSN 2320-3862 JMPS 2016; 4(6): 173-180 © 2016 JMPS A review on ethnomedicinal, phytochemical and Received: 23-09-2016 Accepted: 24-10-2016 pharmacological properties of niruri

Dr. Hakim Md. Kamruzzaman Hakim Said Eastern Medical Dr. Hakim Md. Kamruzzaman and Dr. Md. Obydul Hoq College & Hospital, Dhaka, Bangladesh Abstract Dr. Md. Obydul Hoq Phyllanthus niruri Linn. Belongs to Euphorbiaceae family and it is a small herb having wide range of Hakim Said Eastern Medical medicinal properties, and it is used widely across the world. In Indian ayurvedic and Unani system it is College & Hospital, Dhaka, used for Jaundice, ulcers, skin diseases, diabetes, chest pain and urinary complications. Its taste is bitter Bangladesh and acts as astringent and show laxative effect. This review covers information about ethno medicinal

uses of Phyllanthus niruri in different countries with various pharmacological profile of the . The phytochemical studies were characterized and the presence of various compounds such as lignans, phyllanthin, hypophyllanthin, flavonoids, glycosinoids & tannins was mentioned. The extracts of

Phyllanthus niruri have a wide range of pharmacological activities like antimicrobial, antiviral, hepato protective, antioxidant, anticancer, anti-inflammatory, antiplasmodial and diuretic. This review

summarizes the information about its botanical, morphological, ethnomedicinal, pharmacological and biological activities of the plant. In addition this review provides information about the structure of the

phytochemical compounds that promotes better commercial exploitation.

Keywords: Phyllanthus niruri, phytochemical, pharmacological, hepatoprotective

1. Introduction Bhumyaamalaki (Phyllanthus niruri Schum. & Thonn., Euphorbiaceae), which is widely

spread throughout the tropical and subtropical countries of the world including India is most commonly used in the Indian Ayurvedic system of medicine in problems of stomach, genitourinary system, liver, kidney and spleen. Phyllanthus niruri has been described in Ayurveda by the Sanskrit name – Bhoomyaamalakee, Taamalakee and Bhoodhatree. It was described to have the properties of Rasa, Guna, Veerya and Vipaaka. The Ayurvedic literature

has shown its uses as Kaasahara (antitussive), Shwaasahara (antispasmodic, antidyspnoic), Kaphapittahara (which relieves the Kapha Pitta Dosha), Pipaasaaghna (which relieves Polydipsia), Raktapittahara (hemorrhage disease), Paanduhara (antianemic), Kaamalaahara (which cures jaundice), Kushthaghna (indicated in leprosy), Daahaghna (refrigerant, relieves burning sensation), Kshatakshayaghna (indicated in Trauma) and Mootrarogahara (which

cures urinary disorders). The use of Phyllanthus niruri is gaining momentum because of its novel antiviral activity against hepatitis B virus and for several other biological activities such as kidney and gallbladder stones, for cold, flu, tuberculosis, and other viral infections; liver diseases and disorders including hepatitis, jaundice and liver cancer [1]. It also acts against liver cell toxicity and improves the immune system of patients and has been found effective against

hepatitis A. Phyllanthus niruri is often used in the traditional system of medicine for a variety [2] of ailments including dropsy, diabetes, jaundice, asthma and bronchial infections . In the Ayurvedic system of medicine it is used in problems of stomach, genitourinary system, liver, kidney and spleen. It is bitter, astringent, stomachic, diuretic, febrifuge and antiseptic. The whole plant is used in gonorrhea, menorrhagia and other genital affections. It is useful in

gastropathy, diarrhoea, dysentery, intermittent fevers, ophthalmopathy, scabies, ulcers and wounds. It is also used as a good tonic. The Spanish name ‘chanca piedra’ means “stone breaker or shatter stone.” In South America, ‘chanca piedra’ has been used to eliminate gall bladder and kidney stones, and to treat gall bladder infections, cardiovascular problems, and also a remedy around the world for influenza. Phyllanthus niruri has a long history of use in Correspondence Dr. Hakim Md. Kamruzzaman the treatment of liver, kidney and bladder problems, diabetes and intestinal parasites. In Hakim Said Eastern Medical Suriname (Northeastern part of South America), Phyllanthus niruri is always sold as fresh and College & Hospital, Dhaka, dry plant material in the herb markets. Decoctions are used in herbal baths and after labor, Bangladesh cramps, asthma, uterus complaints and to treat stomachache [3]. ~ 173 ~ Journal of Medicinal Plants Studies

It is a restoration herb and used as an appetizer and as tonic. It this herb to be most effective in the treatment of asthma, is also used as colic. The plant, when boiled with the leaves, is increasing appetite, improving digestion, stimulating liver, and considered to be a diuretic and is used in treatment of diabetes, producing laxative effects. In the Unani System of medicine dysentery, hepatitis, menstrual disorders, and skin disorders. this herb is good for sores and chronic dysentery. Its are Plant extracts are used as blood purifiers, for light malaria used in the treatment of ulcers, wounds, scabies and fevers and anemia. It helps to release phlegm and to combat ringworms. The root of this plant is considered to be an fever. This herb can be used for constipation also. Phyllanthus excellent remedy for liver diseases. niruri elaborates different classes of organic compounds of medicinal importance including alkaloids, flavonoids, hydrolysable tannins (Ellagitannins), major lignans, polyphenols, triterpenes, sterols and volatile oil. Many lignans were isolated from the plant viz., phyllanthin (a bitter constituent) and hypophyllanthin (a non bitter constituent) [4]. The highest amounts of phyllanthin (0.7% w/w) and hypophyllanthin (0.3% w/w) have been reported in leaves whereas, in the stem these are in minor quantities present [5]. Lignans isolated from Phyllanthus niruri are phyllanthin, hypophyllanthin, niranthin, phyltetralin, nirtetralin, isonirtetralin, hinokinin, lintetralin, isolintetralin, demethylenedioxy-niranthin, 5-demethoxyniranthin etc., flavonoïds such as gallocatechin, rutin, quercetin- 3-O-

glucopyranoside, phyllanthusiin, quercetin, kaempferol 3-_-d- Fig 1: Phyllanthus niruri plant. glucopyranoside, kaempferol etc., ellagitannins include geraniin, amariin, furosin, geraniinic acid B, amariinic acid, 3. Botanical description amarulone, repandusinic acid A, corilagin, isocorilagin, Phyllanthus niruri are erect annual herbs, 10–60 cm tall; main elaeocarpusin, phyllanthusiin A, B, C, D and melatonin; stem simple or branched, terrete smooth or scabridulous in securinega-type alkaloids such as isobubbialine and younger parts. Cataphylls, stipules 1.5–1.9 mm long, deltoid epibubbialine and sterol such as amarosterol A, amarosterol B. acuminate blade 1–1.5 mm long, subulate acuminate. Leaves Phyllanthus niruri had been reported to have pharmacological 3–11×1.5–6 mm elliptic oblong obovate, oblong, or even effects such as antimicrobial, antiviral activities against obovate, obtuse, or minutely apiculate at apex, obtuse or hepatitis B, chemoprotective, antimutagenic and slightly inequilateral at base, petioles 0.3–0.5 mm long, hypoglycaemic agent. Methanolic extract of Phyllanthus niruri stipules 0.8–1.1 mm long triangular accuminate. Flowers exhibited immunomodulatory activity. Ellagitannins (geraniin minutes, proximal 2–3 axis with unisexual cymules, each and corilagin) were shown to be the most potent mediators of consisting of 1 male and 1 female or 2–3 males and female or the antiviral HIV activity. Phyllanthin and hypophyllanthin 1 male and 2 females flower or combination thereof; male present in Phyllanthus niruri exhibited antitumor activities flowers pedicals at anthesis ca 1 mm long. Calyx lobe 5, against EAC in Swiss albino mice, cytotoxic effects on K-562 subequal each ca 0.7× 0.3 mm elliptic or oblong elliptic and cells, and hepatoprotective and antioxidant effects. The present abruptly acute at apex hyaline with unbranched mid ribs. Disc review assesses the potential of Phyllanthus niruri in relation segments 5, roundish stames 3 (rarely 2): filaments connate to its traditional uses and in terms of findings based on modern into a column 0.2–0.3 mm high autheros sessile a top bioscientific research. The link between conventional remedies dehiscing longitudinally. Female flowers; pedicles 0.8–1 mm and recent research in various areas has been well established long, obtusely 4-gonous, dialated above, ca 1.5 mm in , in other plants which facilitate to determine effective mode of calyx five lobes, subequal. Lobes sometimes toothed at apex. action of plant derived products. The plant is known to contain Styles 3, free, more or less spreading, and shallowly bifid at several pharmacological important biomolecules whose apex; arms divergent [6]. The capsules on stalks are 1–2 efficacy is well established by several biochemical and mm long, round, smooth, 2 mm wide, with six seeds. When pharmacological studies. This review intent to compile various the fruits burst open the seeds are hurled away. Seeds are studies on this plant and critically evaluates the issues related triangular (like an orange segment); light brown, 1 mm long, to ethnopharmacology, phytochemistry, pharmacology, with 5–6 ribs on the back [7]. clinical studies and toxicology of Phyllanthus niruri. 4. Geographical Distribution 2. General Features It is a field weed which is found proliferating throughout Phyllanthus niruri may be found in profusely branched tropical and subtropical regions of Asia, America, and China. condition along with crops of gram, wheat, pea, etc. In the The genus Phyllanthus (L) Murr. Comprises from 600 to 700 wild it is found growing along road sides, in street corners, and with minor distinguishing features among them. dumps of building materials. Taxonomically, the annual herb Phyllanthus niruri is an annual herb which grows in the wild Phyllanthus niruri belongs to the family of the after first showers of monsoon in Jharkhand, Bihar, order under class Magnoliopsida of the Division Chhattisgarh, etc. states of India. However, it has also been Magnoliophyta. In the Ayurvedic System of medicine the reported to grow commonly in coastal areas. In Indian states it whole plant of Phyllanthus niruri can be used for medicinal usually grows during second week of June and starts bearing purposes. It has been accepted as acrid, cooling, alexipharmic. fruits up to mid-July or August. It remains in the wild up to the Ayurveda recommends its use for bronchitis, leprosy, anaemia, end of the rainy season. However, under safe conditions it can urinary discharge, asthma etc. Local people of Chhattisgarh grow and survive up to mid-winter. and Jharkhand use it for the treatment of skin diseases, indigestion, cough, ulcers etc. Maharshi Charak has considered

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5. Botanical classification glucogallin, quercetin 3-o-b-Dglucopyranosyl-(2 to 1)-o-b-D- Kingdom – Plantae xylopyranoside, b-sitosterol and gallic acid were isolated. Division – Magnoliophyta Structures of these compounds were elucidated on the basis of Class – Magnoliopsida their chemical and spectroscopic data. Order – Euphorbiales Family – Euphorbiaceae 10. Traditional uses Genus – Phyllanthus Phyllanthus has been used in Ayurvedic medicine for over Species – Niruri 2,000 years and has a wide number of traditional uses. This includes employing the whole plant for jaundice, gonorrhea, 6. Vernacular names frequent menstruation and diabetes and using it topically as a Assamese : Holpholi; Poram-lokhi poultice for skin ulcers, sores, swelling and itchiness. The Bengali : Bhui amla plant is bitter, astringent, cooling, diuretic, stomachic, Hindi : Chalmeri, Harfarauri, Bhuiaonla. febrifuge and antiseptic. It is useful in dropsy, jaundice, Kannada : Kirunelli, Nela Nelli, diarrhoea, dysentery, intermittent fevers, and diseases of urino- Konkani : Bhuin-avalae genital system, scabies ulcers and wounds. The young shoots Telugu : Ratsavusirike, Nela Usiri, of the plant are administered in the form of an infusion for the Tamil : Arunelli, Keela Nelli, treatment of chronic dysentery. Its efficacy in the field of Malayalam : Arinelli, Kizhanelli, Nellipuli gastro intestinal disorders like dyspepsia, colic, diarrhoea, Marathi : Rayavali, Bhuiavli, constipation and dysentery is undisputed. In females it is used Oriya : Narakoli as a galactogogue, in leucorrhoea, menorrhagia and mammary Sanskrit : Amala, Bhumyamlaki, abscess. In skin conditions, especially scabby or crusty lesions, Sukshmadala, Vitunika, Bhoodatri. bruises, wounds, scabies, offensive ulcers and sores, oedematous swellings, tubercular ulcers and ringworm, it has 7. Unani Description been utilized with good effect since many years. It is applied Unani name : Bhui Amla, Amlaye Jamen. effectively in intermittent fevers and gonorrhoea as well as in Botanical name : Phyllanthus niruri ophthalmia and conjunctivitis. It has a urolithic property, Synonyms : Amala, Bhumyamlaki, Chalmeri, dissolving renal calculi. Also, used in cough, asthma and other Harfarauri, Bhuiaonla, Bhoodatri. bronchial affections. It’s antifungal, antiviral and Mizaz : Cold & dry in 1st degree. anticancerous properties have also been demonstrated in Maza : Slightly in sour. experimental animals. The powdered leaves of Phyllanthus Boo : Slightly in sourish smelling. niruri (Bahupatra) were used in clinical studies evaluating its Muzir : Due to high dosages, it has bad usefulness in patients suffering from chronic damage to the effect on spleen & urinary bladder. liver due to the protracted hepatitis B virus infection. This type Mukhrij : Expels Safra (Bile). of infection results in inability of the body’s immune system to Nafa-e-Khas : Especially it is effective in hepatic eliminate the virus from the liver cells. This condition is disorders. described as a carrier state, because a continuously harbors the virus. Some of the components of the virus detectable in the 8. Ethnobotany carrier state in the blood are: HBsAg or the surface antigen of Phyllanthus niruri has extensive medicinal properties and has the virus and HBeAg or the envelope antigen of the virus. In long history in the health care system of tropical countries. The addition, the carrier state may be confirmed by the presence of plant is known in traditional health care systems. P. niruri is antibodies directed against the core of the virus or the anti- commonly known as “Chanca pedra” (or) “stone breaker”. HBc antibodies. The powdered leaves of Phyllanthus niruri However there is a lot of confusion about this species were given in form of capsules to the patients with chronic identification. Phyllanthus niruri is used as a folk medicine for viral hepatitis B in a dose of 200 mg three times a day for 30 treating kidney stones, gallbladder stones, liver related days. Phyllanthus niruri treated patients tested negative for the diseases such as liver cancer & jaundice, apart from these it is viral antigen 15-20 days after the end of the treatment. Due to also administered for diuretic, hypoglycemic and hypertension its antiseptic, styptic, carminative, deobstruent, coolant, cases and it also shows anti-inflammatory, anti-tumor, febrifugal, stomachic, astringent and diuretic properties of this antinociceptive and anti-oxidant properties [9]. plant it is very much utilized in traditional medicine.

9. Chemical constituents 11. Pharmacological activity The medicinal plant Phyllanthus niruri Linn. (Euphorbiaceae), Phyllanthus niruri is an important plant of Ayurvedic and its wide variety of phytochemicals and their pharmacological Unani system of medicine in which it is used for problems of properties. The active phytochemicals, flavonoids, alkaloids, the stomach, genitourinary system, liver, kidney, spleen etc. terpenoids, lignans, polyphenols, tannins, coumarins and The medicinal traits and pharmacological activities endorsed saponins, have been identified from various parts of to various parts of Phyllanthus niruri are detailed as follows: Phyllanthus niruri. Extracts of this herb have been proven to have therapeutic effects in many clinical studies [10]. a) Hepatoprotective Effect Hepatitis B is one of the major diseases inflicting human 9.1 Uses of Isolated Phytochemical Constituents Bioassay population. Conventional treatment with interferon –alpha is guided fractionation of boiled aqueous extracts from the whole very expensive and has many serious side effects. Alternative plant of Phyllanthus niruri (Euphorbiaceae) led to the isolation herbal medicine using extracts of Phyllanthus niruri and of 1-o-galloyl-6-o-luteoyl-a-Dglucose, which IC50 values of Phyllanthus urinaria have been reported to be effective against 4.7mg/ml against Babesia gibsoni and 1.4mg/ml against Hepatitis B and other viral infections. A study reports Plasmodium falciparum in vitro. The known compounds b quantitative determination of the anti-viral effect of these

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herbs in well-defined in vitro systems [11]. Phyllanthus niruri of Phyllanthus niruri with DMBA induces skin has been reported to exhibit marked anti-hepatitis B virus papillomagenesis [21]. surface antigen activity in in-vivo and in-vitro studies. Infectious hepatitis is due to the inability of the bodies’ d) Action of kidney stones & uric acid immune system to eliminate the virus from the liver cells: Kidney stone is a common problem that accumulates calcium hence the “carrier state”. An infection with the virus is oxalate crystals, and it includes urinary calculi formation, documented by detectable levels of various viral antigens in nucleation, growth, and aggregation of crystals. Phyllanthus the blood, including HbaAg (the surface antigen of the virus) niruri’s extract interferes in the growth and aggregation of as well as antibodies to the core of virus (HBc antibodies). In calcium oxalate [CaOx] crystals in the calculi. The extract one study, 37 patients with chronic viral hepatitis B were inhibits CaOx crystal aggregation in the early stages of stone treated with a daily dose of 600mg of Phyllanthus niruri for 30 formation in the urine samples of male wister rats. It is days. 59% of the patients lost the HBsAg two weeks after the advisable to treat stone formation in the early stages [22]. The end of the treatment. Furthermore, none of the cases followed CaOx metastable limit was decreased by the treatment of for up to 9 months had any symptoms of HBsAg. The authors Phyllanthus niruri [5% [v/v]] extract and it can also deprive postulated that Phyllanthus niruri might inhibit proliferation of the CaOx crystals and formation of nucleation [23]. The extract the virus by inhibiting replication of the genetic material of the has the ability to prevent the growth of calculi and also change virus [12]. Hepatoprotective effect of an ayurvedic medicine; the shape and texture of the calculi. When treated on the herbal preparation HPN – 12 (containing Glycyrrhiza glabra, preformed calculi it can form a matrix like material on its Picrorhiza kurroa, Berberis aristata, Piper longum, surface and it can modify the appearance and texture of the Phyllanthus niruri, Solanum dulcamara, Zingiber officinale, calculus [24]. The extract is also administered in hyper calciuric Curculigo orchioides, Elettaria cardamomum, Tinospora patients; it can decrease the urinary calcium levels [25] and also cordifolia, Desmodium triflorum and Saccharum officinarum) reduces the excess uric acid in hyperuricemic people by the orally administered to male albino rats at 1ml/100g body lignans with uricosuric action in the extract [26]. weight was found to be effective against liver damage [13]. Animals with Carbon Tetrachloride induced hepatopathy were e) Anti-Inflammatory activity treated with catliv (contains extracts of Swertia chirata, The Hexane Extract (HE), the Lignan-Rich Fraction (LRF), or Eclipta alba, Fumaria vaillantii, Picrorhiza kurroa, the lignans phyltetralin, nirtetralin, niranthin of Phyllanthus Andrographis paniculata and Phyllanthus niruri) at 25ml niruri when given orally inhibited carrageenan (Cg)-induced twice daily orally for six days starting at 48 hours after paw oedema and neutrophil influx. The HE, the LRF or administration of Carbon tetrachloride. On basis of result nirtetralin also inhibited the increase of IL1-β tissue levels obtained it was concluded that the ingredients in catliv, induced by Cg. Bradykinin (BK)-, Platelet Activating Factor effectively helped in regeneration of hepatic cells and is an (PAF)- and endothelin-1 (ET-1)-induced paw oedema were effective liver tonic for calves [14]. Research in Japan and India significantly inhibited by the HE or LRF. Finally, nirtetralin or in the 1980's has demonstrated the liver -healing properties of phyltetralin caused inhibition of paw oedema induced by PAF Phyllanthus niruri. The primary compounds responsible are or ET-1. These results show that the HE, the LRF and the phyllanthin, hypophyllanthin and triacontanal. Glycosides lignans niranthin, phyltetralin and nirtetralin exhibited marked found in Phyllanthus niruri demonstrated Aldose reductase anti-inflammatory properties [27]. (AR) inhibitory activity in studies conducted by a Japanese research group in 1988 and 1989 [15]. f) Antioxidant activity The Total Phenolic Content (TPC) and antioxidant activity of b) Anti-viral activity fresh and dried Phyllanthus niruri were evaluated by Folin- Alcoholic, hexane, chloroform, butanol and water extract of Ciocalteau method, 2,2-diphenyl-1-picrylhydrazyl (DPPH) Phyllanthus niruri were tested for in vitro effects on HbsAg, free radical scavenging activity and Ferric Reducing HBeAg and HBV-DNA in serum samples positive for HBV Antioxidant Power (FRAP) assays. Different drying treatments antigen followed by the screening of the respective antigen by led to significant reduction (p<0.05) in antioxidant properties Elisa. The extract was effective against HBV antigen, the of Phyllanthus niruri methanolic extracts, with microwave butanol extract being the most potent [16]. Further studies were drying causing the highest decrease in TPC and antioxidant conducted on mice infected with wood chuck hepatitis virus activity exhibited by the reduction in both radical scavenging when administrated with extract was effective in three animals activity and FRAP, the boiling water extracts appeared to in reducing the virus within 3-6 weeks eliminating both the exhibit stronger antioxidant potentials (p<0.05) even in dried surface antigen titer and DNA polyemerase activity in serum plant materials. This proves its strong free radical scavenging [17]. An aqueous extract on human hepatocellular carcinoma activity [28]. derived cell at 1 mg mL-1 concentration on a single dose. Inhibition of the secretion of HBsAg for a period of 48 h was g) Anti-spasmodic activity observed [18]. Disruption of hepatitis B virus polymerase Research done in Brazil at the Federal University of Santa activity, mRNA transcription and replication supported the Catarina in 1984 on Phyllanthus niruri revealed an alkaloid role of Phyllanthus niruri being used as an antiviral agent [19]. (phyllanthoside) in the leaves and stem with strong antispasmodic activity. It served as a relaxing agent for smooth c) Anti cancerous & cellular protective actions muscles and they concluded that its spasmolytic action Phyllanthus niruri has high potential to inhibit the growth and probably accounted for the efficacy of Phyllanthus niruri in intiation of cancerous cells which were introduced into mouse expelling stones [29]. skin cells with 7, 12 dimethyl benz (a) anthracene (100μg/100ml acetone) and croton oil (1%) [20] and there is h) Analgesic activity drastic increase in the catalase, reduced glutathione and protein Methanol extract of dried callus tissue at a concentration of levels in the skin. In albino mice the chemopreventive action 10mg/kg, administered intraperitoneally to mice was active vs.

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acetic acid induced writhin and vs. formalin – induced pedal observed that administration of triton in rat caused increase in edema. The extract, at 50mg/kg was inactive vs tail flick serum cholesterol by 3.5 fold, phospholipid 2 fold and response to radiant heat. Ethanol/ water (1:1) extract of dried triglyceride 1.2 fold. Administration of Phyllanthus niruri at entire plant at a dose of 50mg/kg, administered intragastric to the dose of 200mg/kg simultaneously with triton lowered the male mice was active. The extract also administered level of total cholesterol, phospholipid and triglyceride by 27, intraperitoneally to male mice at a dose of 0.3mg/kg was 25 and 24 percent respectively. In an experiment with active. In both cases antinociceptive effects were demonstrated cholesterol fed rats, Phyllanthus niruri at a dose of 100 mg/kg using 5 different models of nociception [30]. lowered the elevated level of low-density lipoprotein lipids in hyperlipidemic and drug fed animals [36]. i) Antibacterial activity The antibacterial activity of extracts of the root and leaf was o) Anticonvulsant Activity assessed against extend spectrum lactamase (ESBL) producing Epilepsy is a major neurological disorder characterized by the Escherichia coli isolated from the stool samples of HIV sero- occurrence of recurrent seizures. The two widely proposed positive patients using Bauer disc diffusion method. The mechanisms involve alterations in the voltage – dependent ion strains isolated from both HIV sero-positive patients were channels such as reduction in inhibitory GABA - mediated susceptible to various concentrations of the extracts (5, 10, 20, drive or increase in excitatory glutamate mediated inputs. This 40 and 80 mg mL-1). This proves the antibacterial activity of chronic progressive CNS disorder affects a large population of the extract [31]. the world. In search of herbal treatment, aqueous and ethanolic extract of Phyllanthus niruri were evaluated for anticonvulsant j) Immune modulatory actions effect using pentylenetetrazole (PTZ) and maximal An arabinogalactan (AG) which was obtained from electroshock - induced seizures (MES) in swiss albino rats. Phyllanthus niruri tea preparations was found to have The result showed ethanolic and aqueous extract of leaves and immunological properties and is tested with peritoneal mice stem of Phyllanthus niruri significantly effective in abolishing macrophages. The glycoside showed the same activity when hind limb extension induced by MES as well as PTZ induced subjected to acidic and neutral gastric conditions using human seizures [37]. gastric fluids and aq. HCL solution [32]. p) Chemoprotective Activity k) Aphrodisiac activity The chemoprotective activity effect of 75% methanolic extract The effect of methanolic extract of the leaves of Phyllanthus of the Phyllanthus niruri plant was studied against niruri on the hormonal parameters of male guinea pigs was cyclophosphamide (CTX) induced toxicity in mice. investigated. The hormonal parameters investigated were Administration of CTX produced significant testosterone, leutinizing and follicle stimulating hormone. myelosuppression as seen from the decreased WBC count and Methanolic extract of Phyllanthus niruri leaves (50–800 bone marrow cellularity. Administration of Phyllanthus niruri mg/kg) caused a statistically significant increase in the level of extract at doses 250 and 750 mg/kg body weight significantly testosterone of the male guinea pigs, from 2.3 ± 0.06 to 3.9 ± reduced the myelosuppression and improved the WBC count, 0.05, 4.3 ± 0.6 and 2.8 ± 0.6 after the 7th, 14th and 21st day of bone marrow cellularity as well as the number of maturing the administration of the extracts, respectively. Furthermore, monocytes that accounted for its chemoprotective activity. In the methanolic extract of Phyllanthus niruri (800 mg/kg) addition, extract from the plant of Phyllanthus niruri was caused an insignificant change in the level of luteinizing (LH) found to decrease the activity of phase I enzyme that showed and follicle stimulating (FSH) hormones from 3.1 ± 0.22 and potent chemoprotective potential of the plant [38]. 1.6 ± 0.50 to 3.0 ± 0.08 and 1.5 ± 0.13, respectively [33]. q) Diuretic Activity l) Anti-ulcer activity The diuretic, hypotensive and hypoglycemic effects of The acidic heteroxylan and another polysaccharide showed Phyllanthus niruri on human subjects were assessed. anti-ulcer activity. These compounds reduced the gastric Appropriate parameters have been studied in the blood as well lesions induced by 65% and 78% ethanol. Phyllanthus niruri as urine samples of the patients. In addition, the physiological proved to be efficient against peptic ulcers [34]. profile and dietary pattern before and after the treatment period were assessed. Interestingly, a significant increase in urine m) Contraceptive effect volume, urine and serum Na levels was observed after Antifertility effect of an alcoholic extract of the whole plant of treatment with Phyllanthus niruri extract. A significant Phyllanthus niruri at a dose of 100 mg/kg body weight for 30 reduction in systolic blood pressure in non-diabetic days orally was investigated in cyclic adult female mice. The hypertensive subjects was noted that further confirmed its results revealed no significant change in absolute body and diuretic property [39]. organ weights in extract fed animals indicated no alteration in general metabolic status. Cohabited females with normal male 12. Dosage mice were unable to become pregnant as their cyclicity was Adults (18 years and older) affected. These factors are related to a change in the hormonal  Generally, an infusion or weak tea of Phyllanthus niruri milieu that governs female reproductive function. Upon has been taken by mouth. Traditionally, individuals drink withdrawal of feeding for 45 days, these effects were 1-3 cups daily or weekly. Some pharmacies in South reversible. Thus, this extract manifests a definite contraceptive America sell concentrated extracts with a daily dose of 2- effect in female mice [35]. 6 milliliters, taken twice or thrice daily.  To treat acute viral hepatitis, 900 milligrams of powdered n) Lipid Lowering Activity Phyllanthus niruri capsules has been taken by mouth three Lipid lowering activity of Phyllanthus niruri alcoholic extracts times daily for seven days. in triton induced hyperlipidaemia was examined in rats. It was  To treat diabetes, 100 milliliters of Phyllanthus niruri

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extract has been taken by mouth twice daily for one week. healthcare professional, including a pharmacist. Additionally, two pellets of Phyllanthus niruri, each 0.8 Medication adjustments may be necessary. grams, have been taken three times daily by mouth for 10  Phyllanthus niruri may increase the risk of bleeding when days. taken with drugs that increase the risk of bleeding. Some  To treat hepatitis B, 200-1,100 milligrams of dried examples include aspirin, anticoagulants (blood thinners) Phyllanthus niruri has been taken by mouth three times such as warfarin (Coumadin®) or heparin, antiplatelet daily for up to three months. drugs such as clopidogrel (Plavix®), and nonsteroidal  To treat high blood pressure, two 0.8-gram pellets have anti-inflammatory drugs such as ibuprofen (Motrin®, been taken by mouth three times daily for 10 days. Advil®) or naproxen (Naprosyn®, Aleve®).  To treat liver disease, three grams of Phyllanthus niruri  Phyllanthus niruri may cause low blood pressure. Caution powder has been taken by mouth three times daily for 30- is advised in people taking drugs that lower blood 45 days. pressure.  To treat urinary stones, 450 milligrams of Phyllanthus  Phyllanthus niruri may increase the amount of drowsiness niruri has been taken by mouth three times daily for three caused by some drugs. Examples include benzodiazepines months. Children (under 18 years old) such as lorazepam (Ativan®) or diazepam (Valium®),  There is no proven safe or effective dose for Phyllanthus barbiturates such as phenobarbital, narcotics such as niruri in children. codeine, some antidepressants, and alcohol. Caution is advised while driving or operating machinery. 13. Side Effects and Warnings  Phyllanthus niruri may interact with agents for  In general, side effects were lacking in human studies. inflammation, pain relief, or wound healing; agents that Phyllanthus niruri is likely safe when taken up to 400 alter immune function; agents that damage the liver; milligrams three times daily for one month, under the care agents that increase urine output; agents that inhibit of a healthcare practitioner. angiotensin-converting enzyme (ACE), angiotensin-  Phyllanthus niruri may lower blood sugar levels. Caution converting enzyme receptor (ARB), or endothelin; agents is advised in people with diabetes or hypoglycemia, and in that mimic acetylcholine (a neurotransmitter); agents that those taking drugs, herbs, or supplements that affect blood protect against radiation; agents that protect against toxic sugar. Blood glucose levels may need to be monitored by effects of chemotherapy; agents that treat disorders of the a qualified healthcare professional, including a pharmacist blood, digestive tract, eyes, heart, or kidneys; agents that and medication adjustments may be necessary. treat gout or inhibit xanthine oxidase (enzyme that breaks  Phyllanthus niruri may increase the risk of bleeding. down purine); agents that widen blood vessels; agents Caution is advised in people with bleeding disorders or used for cancer, diarrhea, fever, HIV/AIDS, malaria, those taking drugs that may increase the risk of bleeding. obesity, or urinary stones; antibiotics, antivirals, Dosing adjustments may be necessary. cholesterol0lowering agents, fertility agents, interferons  Phyllanthus niruri may cause low blood pressure. Caution (man-made version of an immune system protein), and is advised in people taking agents that lower blood nonsteroidal anti-inflammatories (NSAIDs, medications pressure. that reduce swelling and pain).  Drowsiness or sedation may occur. Use caution if driving or operating heavy machinery. 16. Toxicology Phyllanthus niruri is low toxic, and it showed toxicity to  Use cautiously in people with liver disease. batrachians and fishes when extract is alcohol and water based.  Use cautiously people taking diuretics, agents that lower It is very less toxic to mammals. cholesterol or agents that affect the immune system.

 Avoid in pregnant or breastfeeding women, or in those 17. Conflicts of Interest trying to become pregnant. The authors declare no conflict of interests.  Avoid in people with known allergy or sensitivity to Phyllanthus niruri their parts, or members of the 18. Conclusion Euphorbiaceae family. Phyllanthus niruri has been used since ages by the folk  Phyllanthus niruri may also cause abdominal pain or because of its rich medicinal values. The broad spectrum of its discomfort; altered immune system function; altered medicinal use accounts for the chemical investigation of the levels of certain white blood cells; anorexia; chills; herb. Hence, the chemical standardization of the raw material diarrhea; disturbed sleep; dizziness; enlarged lymph and the formulations containing Phyllanthus niruri is under nodes; fatigue; fever; headache; hives; increased sodium, vast discovery and thus more work is required to establish potassium, and chloride in the urine; increased urine Phyllanthus niruri as a useful herb for treatment of various volume; joint pain; lung disease; malaise (discomfort); complications. Coupled with improvements in approaches for muscle pain; nausea; rash; skin prickling; and sore mouth. natural-product isolation, characterization and synthesis, this could be opening the door to a new era in the investigation of 14. Pregnancy and Breastfeeding natural products in academia and industry.  There is a lack of scientific evidence on the use of Phyllanthus niruri during pregnancy or breastfeeding. 19. Acknowledgements The authors acknowledge the inspired provided by Dr. Alhaj 15. Interactions with Drugs Hakim Md. Yousuf Harun Bhuyan, honorable chief  Phyllanthus niruri may lower blood sugar levels. Caution mutaowalli & managing director, Hamdard Laboratories is advised when using medications that may also lower (Waqf) Bangladesh, Dr. Hakim Rafiqul Islam honorable senior blood sugar. People taking drugs for diabetes by mouth or director of marketing, Hamdard Bangladesh, Kazi Mansur-Ul- insulin should be monitored closely by a qualified Huq, Honorable Chairman, Managing Committee, Hakim Said

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Eastern Medical College & Hospital and Director Information Indian J Pathol. Microbiol, 1996; 39:211-215. and Public Relation - Hamdard Bangladesh and Lt. Colonel 18. Lee CD, Ott M, Thayagarajan SP, Shafritz DA, Burk RD, Mahbubul Alam Chowdhury (Ret:), Honorable Director, Gupta S. Phyllanthus niruri down-regulates hepatitis B Hamdard Foundation Bangladesh, for the preparation of this virus mRNA transcription and replication. Eur. J Clin. manuscript. Invest, 1996; 26:1069-1076. 19. Priyanka Sharma, Jyoti Parmar, Preeti Verma, Priyanka 20. Reference Sharma, PK Goyal. Anti-tumor Activity of Phyllanthus 1. Unander DW, Herbert HB, Connete JL, Robert TM. niruri (a Medicinal Plant) on Chemical-induced Skin Cultivation of Phyllanthus niruri and evaluation of Carcinogenesis in Mice. Asian Pacific Journal of Cancer variable potentially affecting yield and the inhibition of Prevention, 2009; 10:1089. viral DNA polymerase. Economic Botany 1993; 47:79-88. 20. Priyanka Sharma, Jyoti Parmar, Preeti Verma, Priyanka 2. Foo LY, Wong H. Phyllanthusiin D, unusual hydrolysable Sharma, Goyal PK. Chemopreventive effect of tannin from Phyllanthus niruri. Phytochemistry 1992; Phyllanthus niruri on DMBA induced skin 31:711-713. papillomagenesis in swiss albino mice. Int J Biol Med 3. May AI. Surinaams Kruidenboek. Sranan Oso Dresi. Res. 2010; 1(4):158-164. Surinamese Book of Herbs. Uitgeverij Vaco, Paramaribo- 21. Barros ME, Schor N, Boim MA. Effects of an aqueous Suriname, 1982, 80. extract from Phyllanthus niruri on calcium oxalate 4. Row LR, Satyanarayana P, Subba Rao GSR. Crystalline crystallization in vitro. Urol Res 2003; 30:374. constituents of Euphorbeaceae – the synthesis and 22. Ramsout R, Rodgers A, Webber D. Investigation of the absolute configuration of phyllanthin. Tetrahedron 1967; effects of Phyllanthus niruri on in vitro calcium oxalate 23:1915. crystallization, European urology supplements 2011; 5. Sharma A, Singh RT, Anand S. 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